To Evaluate The Effect Of Ketoconazole, Ritonavir and Erythromycin on the Safety and Pharmacokinetics of Avanafil
Information source: VIVUS, Inc.
Information obtained from ClinicalTrials.gov on February 12, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Erectile Dysfunction
Intervention: Ritonavir (Drug); Ketoconazole (Drug); Erythomycin (Drug); Avanafil (Drug); Avanafil (Drug); Avanafil (Drug)
Phase: Phase 1
Status: Not yet recruiting
Sponsored by: VIVUS, Inc.
Official(s) and/or principal investigator(s):
Shiyin Yee, PhD, Study Director, Affiliation: VIVUS, Inc.
This study is being conducted to examine the effect of three CYP3A4 inhibitors (ketoconazole,
erythromycin and ritonavir) on the single dose pharmacokinetics of avanafil. Ketoconazole and
ritonavir are potent inhibitors of CYP3A4 and erythromycin is a moderate CYP3A4 inhibitor.
Any interaction that is observed would be predictive of other inhibitors of CYP3A4.
Official title: A Phase I, Single-Centre, Open-Label, Randomized, One-Sequence Crossover, Three-Group Study to Evaluate the Effect of Ketoconazole, Ritonavir and Erythromicin on the Safety and Pharmacokinetics of Avanafil (TA-1790) in Healthy Male Subjects
Study design: Treatment, Randomized, Open Label, Crossover Assignment
Primary outcome: Evaluate the safety of avanafil when administered with Ketoconazole, ritonavir, or erythromycin and to assess the effect of co-administration of these drugs on the pharmacokinetics of avanafil
Erectile dysfunction (ED) is the persistent or recurrent inability to attain and maintain
penile erection sufficient to permit satisfactory sexual performance. The current first-line
treatment for ED consists of oral therapy with phosphodiesterase type 5 (PDE5) inhibitors.
These drugs prevents the hydrolysis of cyclic guanosine monophosphate (cGMP), resulting in
increased levels of cGMP and decreased Ca+2 concentrations in the smooth muscle cells of the
erectile tissues, smooth muscle relaxation and increased blood flow into the penis. The drugs
are extensively metabolized in human liver microsomes, and involve the cytochrome P450, CYP2C
subfamily and CYP3A4. This enzyme system is readily inhibited by many drugs. When enzymes
that metabolize PDE5 inhibitors are inhibited, there may be increased plasma concentrations
of the drugs and possible increases in or prolongation of therapeutic and/or adverse
Avanafil is a potent and highly specific PDE5 inhibitor that is rapidly absorbed from the
gastrointestinal tract and that has a relatively short half-life (0. 55-1. 2 hours). The
formation of the main metabolites of avanafil is catalyzed by CYP3A4. It is possible that the
pharmacokinetics of avanafil may be modified by drugs that block the cytochrome P450 enzyme
pathways, resulting in significant changes in its pharmacokinetic (PK), efficacy and adverse
event profiles. This study is being conducted to examine the effect of three CYP3A4
inhibitors (ketoconazole, erythromycin and ritonavir) on the single dose pharmacokinetics of
Ketoconazole and ritonavir are potent inhibitors of CYP3A4 and erythromycin is a moderate
CYP3A4 inhibitor. Any interaction that is observed would be predictive of other inhibitors of
Minimum age: 21 Years.
Maximum age: 45 Years.
1. Males, 21 to 45 years of age (inclusive).
2. A body weight of at least 50 kg and a body mass index (BMI) between 21 and 28 kg/m2,
3. Medically healthy, with clinically insignificant screening results [e. g., laboratory
profiles, medical histories, ECGs, physical exam, etc., in the opinion of the
4. Subjects are able to communicate with the investigator, and to understand and comply
with all requirements of study participation.
5. Voluntarily consent to participate in the study
6. The subject must agree not to donate his sperm during and within 3-months of the
completion of the study.
7. All sexually active male subjects and their female partners of childbearing potential
must agree to use adequate contraception methods, for the specified time.
1. A history or presence of significant cardiovascular, neurological, hematological,
psychiatric, hepatic, gastrointestinal, pulmonary, endocrine, immunologic or renal
disease or other condition known to interfere with the absorption, distribution,
metabolism, or excretion of drugs or place the subjects at increased risk as
determined by the investigator.
2. Any clinically significant laboratory abnormalities as judged by the investigator.
3. Systolic blood pressure < 90 or >140 mmHg; diastolic blood pressure < 50 or > 90 mmHg
at screening or at check-in on day 1 in treatment period 1.
4. Positive urine drug test and/or positive breath alcohol test.
5. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen
(HBsAg), or hepatitis C antibodies (HCV) at screening.
6. Any history or presence of alcoholism or drug or substance abuse.
7. Allergy to or previous adverse events with PDE5 inhibitors, ketoconazole, ritonavir
and/or erythromycin or their constituents.
8. Use of any prescription or over-the-counter (OTC) medication, including herbal
9. Use of any drugs known to have clinical significance in inhibiting or inducing liver
enzymes involved in drug metabolism
10. Blood donation or significant blood loss.
11. Any use of tobacco or nicotine products within 6 months.
12. Any history of celiac diseases, food allergies, and those on vegetarian or other diets
incompatible with study objectives.
13. Any subject who received an investigational drug within 30 days .
14. Clinical judgment by the investigator that the subject should not participate in the
Locations and Contacts
Research Site, Lincoln, Nebraska 68502, United States
Starting date: October 2008
Last updated: October 21, 2008